ClinVar Miner

Submissions for variant NM_004974.4(KCNA2):c.889C>T (p.Arg297Trp)

dbSNP: rs1649473972
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001268184 SCV001446912 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001382054 SCV001580661 pathogenic Developmental and epileptic encephalopathy, 32 2024-04-25 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 297 of the KCNA2 protein (p.Arg297Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (EIEE) (PMID: 28806589, 29100083, 31170314). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 986989). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNA2 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg297 amino acid residue in KCNA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25477152, 25751627, 27733563, 29050392, 30283815). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center RCV001382054 SCV002579248 pathogenic Developmental and epileptic encephalopathy, 32 2022-06-03 criteria provided, single submitter clinical testing

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